Three neuropsychiatrists dig into the mixed research behind menopause, hormone replacement therapy, and dementia risk.
By 2050, around 135 million people worldwide will be living with dementia. The most common cause of dementia is Alzheimer’s disease. Women are more likely than men to develop Alzheimer’s disease, even after accounting for women living longer. The symptoms of Alzheimer’s disease most commonly occur after the age of 65. However, changes in the brain begin decades before symptoms start. For women, this typically coincides with their transition to menopause.
Menopause results from the body decreasing production of two hormones made by the ovaries: estrogen and progesterone. These hormonal changes are associated with a wide range of symptoms, including hot flushes, night sweats, difficulties sleeping, reduced libido, mood changes and brain fog.
Menopause hormonal therapy (also called hormone replacement therapy or HRT), including estrogen alone or estrogen combined with a progesterone, has been prescribed to help with menopausal symptoms for decades.
But how does menopause hormone therapy affect the risk of dementia? And why do some studies say the therapy increases the risk, while others say it reduces it?
Can Hormone Replacement Therapy Prevent Menopause Brain Changes?
Hormones and the brain
A large body of pre-clinical (animal based) research shows estrogen helps protect the brain. It reduces any damage to nerve cells and supports overall brain health. Receptors that respond to estrogen are in areas of the brain related to reproductive functions. But they’re also in areas of the brain important for learning, memory and higher-order cognitive abilities such as planning, organization and decision making.
The loss of the “neuroprotective” effects of estrogen after menopause is thought to contribute to more cases of Alzheimer’s disease in women than men.
Clinical studies have also shown women who have a medical or surgical menopause before the age of natural menopause have a higher lifelong risk of dementia and cognitive impairment. This risk appears to be reduced in women who take estrogen therapy after their surgery.
This has led researchers to hypothesize that adding estrogen back – via menopause hormone therapy – might protect and maintain women’s cognitive health.
However, the research findings have not been consistent.
Q&A: What Can Hormone Replacement Therapy Do for Brain Health?
Could menopause hormone therapy impact dementia risk?
Concern about dementia risk and menopause hormone therapy have been partially driven by the unexpected findings from a landmark study conducted more than two decades ago.
The findings showed hormone therapy use in post-menopausal women, 65 years and older, was associated with an increased risk for dementia.
However, these studies have some key limitations:
- Most of the women were aged over 65 and more than ten years post-menopause.
- The type of estrogen and progestogen (a synthetic form of progesterone) used may have less benefit on brain health.
The most recently published systematic review and meta-analysis of scientific data linking hormone therapy to the risk of Alzheimer’s disease included findings from 51 different reports that were published up to 2023.
The results showed if hormone therapy was initiated in midlife, or more generally within ten years of the final menstrual period, there was a decreased risk of later-life Alzheimer’s disease compared to women not using any hormone therapy.
The greatest reduction in risk was associated with estrogen-only hormone therapy.
In contrast, when considering using hormone therapy in late-life, or more than ten years after menopause, estrogen-only therapy had a neutral effects on Alzheimer’s disease risk.
However, estrogen-progestogen therapy was associated with a risk increase.
Only one clinical trial has been published since this meta-analysis. This study examined the long-term effects of menopause hormone therapy use initiated in early menopause.
Women were on average aged 52.8 years and 1.5 years post-menopause when they entered this trial. They were randomly assigned to an estrogen (with or without progestogen) or placebo for four years. Researchers followed 275 women up ten years later. They found no cognitive effects (no harm nor any benefit) based on whether women were exposed to 48 months of hormone therapy or a placebo.
Q&A: Women’s Brain Project CEO on Sex, Gender, and Alzheimer’s
What affects your risk?
It appears the effects of menopause hormone therapy on dementia risk are influenced by several factors. These include when someone starts taking it, how long they take it for, the type of hormones used, and the person’s genetic and health background.
- When therapy starts: the “critical window” hypothesis. One key factor in determining the effect of menopause hormone therapy on cognitive function and the risk of dementia appears to be when therapy starts relative to menopause. This is called the “critical window hypothesis.” According to this hypothesis, estrogen may help protect neurons in the brain only if started early in the menopause transition, particularly within a few years of menopause, when the brain may still be more responsive to hormones.
- Type of menopause hormone therapy and the role of progesterone. The type of hormones included in hormone therapy can vary widely in their molecular structure as well as their physiological actions. Different types of estrogens (such as estradiol or conjugated estrogen) and the inclusion of a progestogen (needed for women who have not undergone a hysterectomy) may have different impacts on brain health and dementia risk. Some studies suggest adding a progestogen to estrogen therapy could counteract some of the cognitive benefits of estrogen alone, possibly by blocking estrogen receptors in the brain.
- The role of vasomotor symptoms. Vasomotor symptoms, such as hot flushes and night sweats, are the hallmark of menopause. Experiencing more vasomotor symptoms has been linked to poorer memory as well as an increase in biological markers associated with dementia risk. Therefore, one possible pathway by which menopause hormone therapy may moderate Alzheimer’s disease risk is via their effects on reducing vasomotor symptoms.
- A person’s genetic and health background. The greatest genetic risk factor for older-onset Alzheimer’s disease is carrying one or more copies of a specific version of the APOE gene, called APOE4. There is an emerging hypothesis that women who have this genetic risk for Alzheimer’s disease may show the greatest benefit from using hormone therapy.
STUDY: In Menopause, Estrogen Drops — Here’s How the Brain Reacts
What does this mean for you?
The clinical and scientific community are still debating whether menopause hormone therapy may play a role in Alzheimer’s disease risk.
Overall, the decision to use hormone therapy should be individualized, taking into account your age and timing of menopause, health status and specific menopause symptoms.
We need more research before we can make clear decisions about the role of hormone therapy and dementia risk, but based on the current evidence, hormone therapy may be beneficial if started early in the menopause transition, particularly for women at genetic risk of Alzheimer’s disease.
You lose all credibility when you reference the women’s health initiative. It’s been widely shown to have been badly conducted research and the scientists have had to make a public apology.
This article was written by a group of scientists about their own research — click through the links in the very last paragraph of the piece for their contact information if you would like to send them a comment directly. To your point about women’s health research, indeed, it’s been handled poorly (if not just un-thoroughly), across science, for decades! The more gold-standard, peer-reviewed, credibly published studies there are out there, the more data future scientists have to reference as they work to complete what’s currently a woefully incomplete picture of sex as a biological variable. (More articles on sabv at https://www.beingpatient.com/tag/sabv/ if you’re interested.) Thanks for reading and commenting.
I am unusual in that I went on to HRT after menopause when all my PMS symptoms returned.In addition I had Zoladex.For the past 10 years I have been on Oestrogel plus Cyclogest pure progesterone which pre- menopause controlled my severe PMS.
For me, whenever I encountered cognitive sluggishness additional cyclogest rectified the situation and still does.
Would hope this could be trialled.
You can’t trust any of the studies because none of the studies take into consideration the diet and lack of nutrients. Some people have better diets than others. Which means someone who has lived 60 years with say a lack of choline and folate they are highly more likely to develop dementia in old age. I would be interested to know what the dementia rates was with the Chinese and Japanese women compared to ours.
This article was written by a group of scientists about their own research, and you’re welcome to click through the links in the very last paragraph of the piece for their contact information if you would like to send them a comment directly. But to your point here – yes! Diet is an important variable, as is exercise, as are other aspects of lifestyle — and indeed, variables in general make any observational study difficult. Scientists with peer-reviewed, credibly published research have worked hard to account for those variables and their study methodology. The important thing to remember here is that science is a matter of consensus. If many studies over a long period of time show the same results, gradually emerges the possibility of “proof.” If a large number of scientists around the world have found the same conclusion over decades of research, that’s where we put our trust. If you’re interested in diet as a variable, check out this piece – https://www.beingpatient.com/can-a-healthy-diet-really-prevent-dementia/?utm_source=organic&utm_medium=social . Thanks for reading!